Arachidonic acid serves as the biological precursor for a family of physiologically active eicosanoids. These eicosanoids include products derived from the metabolism of arachidonic acid, the two major routes of which are the lipoxygenase pathway and the cyclooxygenase pathway.
Lipoxygenase pathway products such as leukotrienes (LT), function as regulators of allergic and inflammatory reactions. Dorland's Illustrated Medical Dictionary, 27th Ed., W. B. Saunders Co., Phila., Pa., (1988) Leukotrienes are identified by letters with subscripts indicating the number of double bonds in the molecule. Id. Some leukotranes, e.g., LtB.sub.4, stimulate the movement of leukocytes, while others, e.g., LTC.sub.4, LTD.sub.4, and LTE.sub.4, constitute slow reacting substance of anaphylaxis (SRS-A), which causes bronchial constriction and other allergic reactions. Id. The role of leukotrienes according to J. Feher, G. Csomos and A. Vereckei ("Free Radical Reactions in Medicine", Springer Verlag, Berlin, Heidelberg, New York, Tokyo, 1987, p. 29) is important in the regulation of neutrophil and eosinophil function, chemotaxis, chemokinesis, stimulation of guanylate cyclase, modest release of lysosomal enzymes, humoral activities, contraction of smooth muscle, alteration in the permeability of microvasculature, constriction of peripheral pulmonary airways and trachea.
The cyclooxygenase pathway leads to the cyclic endoperoxides (PGG and PGH) and subsequent metabolic products. The inhibition of their biosynthesis is now widely recognized as a mechanism of the nonsteroidal anti-inflammatory drugs such as aspirin. Goodman and Gillman's "The Pharmacological Basis of Therapeutics," MacMillan Publishing Co., New York, N.Y. 7th Ed., Ch. 28, (1985). One of the limitations of the aspirin-like drugs is their inability to inhibit the metabolism of arachidonic acid by lipoxygenases. Id at 663. It is believed that inhibition of cyclooxygenase can lead to increased formation of leukotrienes, which may play a role in the production of symptoms of hypersensitivity in some individuals following the administration of aspirin and aspirin-like drugs. Id.
U.S Pat. No. 4,708,964 discloses compounds unrelated to dihydroquinoline useful for the inhibition of lipoxygenase in humans. As inhibitors of lipoxygenase, these compounds are disclosed to be useful in the treatment of psoriasis, cell proliferation, skin allergies, insect bites, allergic rhinitis, conjunctivitis, hay fever, bronchial asthma, allergic gastroenteritis, uterine contractions, hyperactivity of the colon and bronchospasms.
It is known from the publication of D. J. Baumanor et al., "Flavonoids and Related Compounds as Inhibitors of Arachidonic Acid Peroxidase", Prostaglandins, Vol. 20, No. 4, pp 627-637 (Oct 1980) that many flavonoids, incl. Catergan (The Merck Index, Eleventh Edition, 1988), are lipoxygenase and cyclooxgenase pathway inhibitors. However, their use is associated frequency with hemolytic anemia of fatal outcome, so e.g. Catergan was neither withdrawn from the clinical practice or its application had been strongly limited in several European countries, including Hungary.
Carethers et al. in a series of patents, of which U.S. Pat. No. 4,921,871 is illustrative, disclose enolamides which inhibit lipoxygenase or the biosynthesis or biochemical action of leukotrienes and, therefore, are taught as useful in the treatment or amelioration of a number of diseases whose pathogenesis involves the production of the leukotrienes and other lipoxygenase-derived products. These lipoxygenase inhibitors aid in the prevention of tissue damage and inflammation which result from infiltration of leukocytes, release of tissue digesting lysosomal enzymes, and changes in the permeability and contractile state of smooth muscle tissue. Carethers et al. further discloses specific conditions in which such lipoxygenase-inhibiting or leukotriene-antagonizing compounds and pharmaceutical compositions are useful and these include allergy, asthma, arthritis, skin disorders including psoriasis and acne, inflammation, inflammatory bowel diseases, pain, and cardiovascular disorders including myocardial ischemia and infarction, angina, arrhythmias, stroke, and atherosclerosis.
U.S. Pat. No. 4,568,696 discloses combinations of non-steroidal anti-inflammatory compounds useful in the treatment of pain, inflammation, swelling and other related symptoms. Such combinations are inhibitors of both the lipoxygenase and cyclooxygenase pathways, and it is theorized, that this inhibition of both pathways, is the mechanism by which the compounds of this disclosure reduce and control pain and inflammation.
It is known from the Hungarian patent specification No. 162,358 or the equivalent British patent specification No. 1,390,991 or the equivalent German patent specification No. 2,265,400 that 2,2,4-trimethyl-1,2-dihydroquinoline and its substituted derivatives, except the derivatives substituted on the nitrogen and the carbon in position 6 (hereinafter named "acetoanils"), are capable of reacting with aliphatic C.sub.1-4 aldehydes in a condensation reaction. It has also been mentioned in these patent specifications that the dihydroquinoline derivatives thus prepared are highly effective antioxidants or radical scavengers with a very low toxicity. Out of the compounds described in those patent specifications 6,6'-methylene-bis(2,2,4-trimethyl-1,2-dihydroquinoline) (hereinafter referred to as "MTDQ") has been used in the clinical practice as a radio sensitizing agent in the ionization radiotherapy of malignant tumors. In this connection, the following literature references and patent specifications can be cited: U.S. Pat. Nos. 4,025,631 and 4,046,765; Zs. Pollak et al., Strahlentherapie, 154, pages 499 to 502 (1978), a paper publishing a presumable mechanism of action, too in addition to the clinical results; Zs. Pollak et al., Acta Radiol. Scand., 18, pages 97 to 101 (1979); Erdelyi et al., Strahlentherapie, 156, pages 198 to 200 (1980); G. Kovacs, Strahlentherapie, 160, pages 590 to 593 (1984); and A. U. Schratter, Wiener Klinische Wochenschrift, 15, pages 518 to 522 described in the latter article.
Alkaline metal salts of 6,6'-methylene-bis(2,2-dimethyl-1,2-dihydroqulnoline-4-methane sulfonate) derivatives have been described in our published German patent application Ser. No. 3,025,656 or equivalent U.S. Pat. No. 4,356,306 as water-soluble derivatives (hereinafter named "MTDQ-DA"). Borzsonyi et. al., Toxicol. Letters, 7, pages 281 to 285 (1981) stated that MTDQ is liberated in vivo from these compounds showing a protective effect against carcinogens J. Feher et al., Acta Physiol. Hung., 64, pages 401 to 407 (1984) described the hepatoprotective action of these compounds whereas S. Sulyok et al., Acta Physiol. Hung., 64, pages 437 to 44 (1984) reported on an antiatherosclerotic effect.
As a comprehensive work, the dissertation of candidate's degree of Zs. Pollak entitled "Development of a Radiosensitizing Antioxidant and Use Thereof in the Oncoradiologic Practice" (in Hungarian; Library of the Hungarian Academy of Sciences, 1979) can be cited. The following citation is found on page 30 of this dissertation, in the chapter entitled "The Biochemical Conception of the Synthesis of MTDQ": "In the course of our synthetic work it was aimed to maintain the effectivity of the antioxidant and simultaneously, to decrease its toxicity. This was achieved by increasing the molecular weight on the one hand and by taking care, on the other hand, that the ratio of the molecular weight to the number of functional groups would not be higher".
Aliphatic ketones can also be used instead of aliphatic aldehydes in the preparation of compounds of this kind as the following citation is found in Gy. Bruckner's textbook entitled "Organic Chemistry" (Ed. Tankonyvkiado, Budapest, 1954; in Hungarian) Vol. I., page 396: "Ketones show condensation reactions analogous to those of aldehydes".
Recently Javor et al., Int. J. Tiss. React. 1, pages 35 to 40 (1986) reported on the protective action of compounds of the above type on the gastrointestinal mucosa. Zs. Pollak et al., described their utility for the protection from damages induced by free radicals in the acute respiratory insufficiency. MTA Symposion, January 7 and 8, 1986, Szeged, Abstracts of Proceedings, page 27; 6th Congr. Eur. Soc. Pneumonol, Amsterdam from Aug. 31 to Sep. 5, 1987, Subm. Abstr. No. 447,180 and Abstr. No. 275,276 of the 7th Congr. Eur. Pulm. Budapest, from Sep. 4 to 9, 1988.
It should be emphasized that the therapeutic effects listed above are based on the effect exerted on the cyclooxygenase system and within this, on the shift of the prostacyclin/thromboxane balance in favor of prostacyclin. G. Deby-Dupont et al., Intensive Care Med., 13. pages 167 to 174 (1987) refer thereto that, among the therapeutic effects discussed above, the action protecting from the acute respiratory insufficiency is based on this mechanism of action.
It has now been found, that the dihydroquinoline derivatives of this invention, modulate pathways in the metabolism of arachidonic acid. Arachidonic acid pathways include, but are not limited to, cyclooxygenase and lipoxygenase. Thus, the compounds of this invention are useful in the treatment of a wide variety of pathological conditions where products of the pathways of the metabolism of arachidonic acid, i.e. the cyclooxygenase and the lipoxygenase pathways, contribute to the pathogenesis. At the same time, while decreasing the concentration of leukotrienes, they increase the ratio of prostacycline/thromboxane A.sub.2. Moreover, the compounds of this invention unexpectedly normalize the pathologically changed cytochrome C and P 450 values, said latter two compounds being known as the initiators of the toxic generation of oxygen free radicals from molecular oxygen.